New analogs of 19-nor-testosterone, their esters and process of preparation



United States Patent 3,115,507 NEW ANALOGS 0F 19-NOR-TESTOSTERONE,

THEIR ESTERS AND PROCESS OF PREPA- RATlON Gerard Nomin, Noisy-le-See, Robert Bnconrt, Villiersle-Bel, and Andre Pierdet, Noisy-le-See, France, assignors, by mesne assignments, to Roussel-UCLAF, 5A., Paris, France, a corporation of France No Drawing. Filed Jan. 19, 1961, Ser. No. 96,062 Claims priority, application France Jan. 22, 1960 28 Claims. (Cl. 260-4914) The present invention relates to new analogs of 19-nortestosterone, particularly to 18,19-di-nor-lBB-substitutedtestosterones and their esters of the formula:

R L on H 0L1 wherein R represents a radical selected from the group consisting of alkyl having from 2 to 18 carbon atoms, alkenyl having from 2 to 6 carbon atoms, phenylalkoxyalkyl having from 8 to 18 carbon atoms, and aralkyl having from 7 to 18 carbon atoms, and R represents a member selected from the group consisting of hydrogen and the acyl radical of an organic carboxylic acid having from 1 to 18 carbon atoms.

The invention also relates to intermediates produced in the synthesis of 18,19-di-nor-13B-substituted-testosterones and to the process of preparing the same.

These new compounds, the 18,19-cli-nor-13fi-substitutedtestosterones and their esters of the formula:

wherein R represents a radical selected from the group consisting of alkyl having from 2 to 18 carbon atoms, alkenyl having from 2 to 6 carbon atoms, phenylalkoxyalkyl having from 8 to 18 carbon atoms, and aralkyl having from 7 to 18 carbon atoms, and R represents a member selected from the group consisting of hydrogen and the acyl radical of an organic carboxylic acid having from 1 to 18 carbon atoms, have a steric configuration which corresponds to that of the natural steroid products and are possessed with useful physiological properties and have, in particular, an anabolistic activity.

The invention has for its object the production of 18,19-di-nor-13,8-substituted-testosterones and their esters of the formula:

R OR 36 XI wherein R represents a radical selected from the group consisting of alkyl having from 2 to 18 carbon atoms,

3,115,507 Patented Dec. 24, 1963 wherein R has the above assigned values;

COOCH wherein R has the above assigned values;

GOOH CH wherein R has the above assigned values;

wherein R has the above assigned values;

wherein R has the above assigned values;

VII

wherein R and R have the above assigned values;

VIIa

wherein R and R have the above assigned values;

VIII

wherein R and R have the above assigned values and X represents a halogen;

wherein R and R have the above assigned values; and

wherein R and R have the above assigned values.

These and other objects of the invention will become more apparent as the description thereof proceeds.

We have found that 6-methoxy-3,4-dihydronaphthyl- (2,1)-isoxazole of Formula I:

can be substituted by reaction with a halide to give compounds of the Formula IIabove which can be further reacted to give the novel 18,19-di-nor-13/8-substituted-testosterones.

The process of producing the 18,19-di-nor-13/3-substituted-testosterones is outlined in the reaction diagram R g on x XI The process consists essentially in reacting Compound I with a halide of the formula RX wherein R represents a radical selected from the group consisting of alkylv having from 2 to 18 carbon atoms, lower alkenyl having from 2 to 6 carbon atoms, phenylalkoxyalkyl having from 8 to 18 carbon atoms, and aralkyl having from 7 to 18 carbon atoms and X represents a halogen atom, in the presence of an alkali metal lower alkanolate. By this reaction 2-substituted-2-cyano-6-methoXy-tetralones-1 of the general Formula II are obtained:

wherein R has the above assigned values.

By tetralone we mean a 1,2,3,4-tetrahydronaphthalene substituted in the 1-position by an oxo group.

The process of the invention is preferably carried out by (a) dissolving 6-methoxy-3,4-dihydronaphthyl-(2,1)- isoxazole in an inert organic solvent, preferably a lower alkanol corresponding to the alkali metal lower alkanolate used in the reaction, although other alcohols or other inertorganic solvents may be employed, (b) adding to the solution an alkali metal lower alkanolate, preferably sodium methylate in methanol, (0) thereafter adding a halide of the formula-RX wherein R and X have the.

previously assigned meanings and (d) isolating the desired tetralone-1 of Formula II by conventional extraction methods. The reactions are preferably carried out in an inert atmosphere at about room temperature. Since the reactions are exothermic, some elevation of temperature occurs. No special conditions of cooling, however, need be observed.

Among the halides of the formula RX which may be employed are the alkyl halides having from 2 to 18 carbon atoms, such as n-propyl iodide, ethyl bromide, isobutyl iodide, etc., the lower alkenyl halides having from 2 to 6 carbon atoms, such as allyl bromide, 2-butenyl-1 iodide, etc., and the substituted alkyl halides, such as phenylalkoxyalkyl bromides, l-bromo-l-benzyloxy-methane.

A particular method of execution of the process consists in preparing 2-cyano-2-n-propyl-6-methoxy-tetralone- 1 (Formula II, R=CH CH -CI-I by the introduction of the allyl radical into 6-methoxy-3,4-dihydronaphthyl-(2,1)-isoxazole, followed by a catalytic hydrogenation of the 2-al1yl group to give the corresponding 2-n-propy1 derivative. The catalytic hydrogenation is preferably conducted in the presence of a reduced palladium catalyst such as palladized carbon black at room temperature and pressure utilizing an inert organic solvent such as ethanol.

The 2-cyano-2-substituted-6-methoxy-tetralone-1, II, so produced, is condensed with dimethyl succinate in the presence of an alkaline condensation agent, such as an alkali metal alkanolate dissolved in the same alcohol. The condensation produced, the S-methoxy-BB-substituted-l5-methoxycarbonyl-A -des A-gonatetraene-17- one, III, resulting, is subjected to a reduction with consecutive saponification by an alkali metal borohydrlde in an inert aqueous organic solvent at reflux temperatures to obtain the 5 methoxy 13 B substituted 15 carboxy- A -des A-gonatetraene- 7B-ol, IV. his last compound is resolved into its optically active antipodes by formation of an insoluble salt between a dextrorotatory base, such as dextrorotatory chloramphenicol, and the levorotatory enantiomorph of compound IV, followed by separation and hydrolysis of the salt formed.

The levorotatory compound, IV, is next decarboxylated by heating to reflux in an inert organic solvent with hydrochloric acid. S-methoxy-13B-substituted-A -des A- gonatetraene-Ufi-ol, V, is obtained. The double bond 14, 15 of this last compound is reduced by catalytic hydrogenation to give S-methox -l3fi-substituted-A des A-gonatriene-l7B-ol, VI.

On reduction of the aromatic ring B of Compound VI by means of sodium in liquid ammonia, the l3fi-substituted-A -des A-gonene-17fl-ol5-one, VII, is prepared, which is esterified in the 17-position, preferably by benzoic acid, then the S-ketone group is transformed into the pyrrolidylenamine.

The 5 pyrrolidyl 13B substituted 176 acyloxy- A -des A-gonadiene, VIIa, thus obtained is condensed with a 1,3-dihalo-2-butene, such as 1,3-dichloro-2- butene or 1-iodo-3-chloro-2-butene, and the condensation product, a 3-halo-l3B-substituted-17fi-acyloxy-4,5- seco-A -gonadiene-5-one, VIII, is next hydrolyzed by means of a strong acid, such as sulfuric acid, into 13,6- substituted-17B-acyl0xy-4,5-seco-A -gonene-3,5-dione, IX, after which the reduction of the double bond is effected followed by cyclization in an acidic medium of the reduced product to obtain the ester corresponding to the l8,l9-di-nor-lFtp-substituted testosterone which is saponitied to give the free alcohol.

The reduction of the 9(10) double bond of the compound of the Formula IX can be made by catalytic hydrogenation.

The cyclization of compound X is preferably effected in a hydrochloric acid media at room temperature in the absence of light.

By the term gonane and its variations, such as gonene, etc., we mean a compound having fully hydrogenated cyclopentanophenanthrene nucleus and having the steric configuration of the natural steroids. The compounds so named could also be called 18,19-di-nor-androstanes.

In addition to the benzoic acid ester, other esters with organic carboxylic acids having from 1 to 18 carbon atoms, such as the alkanoates and alkenoates, for example, the acetate, the trimethylacetate, the propionate, the 4,4- dimethylpentanoate, the lO-undecenoate; the cycloalkylalkanoates, for example, the ti-cyclopentyl-propionate; the arylalkanoates, for example, the phenyl-propionate; the cycloallcanoates, for example, the hexahydrobenzoate, the hexahydroterephthalate and other phenyl-carboxylic acids, 3,5-dinitrobenzoate, may also be prepared without departing from the scope of the invention. Such other esters are prepared by reacting the corresponding esterifying acid derivatives, such as the acid, acid chloride or acid anhydride.

The invention extends, it is to be understood, to the intermediate products obtained in the present process, particularly in the case of the preparation of 18,19-di-nor- 13 fl-n-propyhtestosterone and its ester with benzoic acid. These specific compounds are:

2-cyano-Z-n-propyl-o-methoxy-tetralone-1, II, R=C H 5-methoxy-13B-n-propyl 15 methoxycarbonyl-A des A-gonatetraene-17-one, II, R=C3H7;

S-methoxy-l35-npropyl-A -des A-gonatetraene-UB- S-methoxy-l3t3-n-propyl-A. des A-gonatriene-l7l3-ol,

13fl-n-propyl-A -des A-gonene 17,8 ol 5 one, VII,

13 ,B-n-propyl-17,8-benzoyloxy-A -des A gonene-S-one, VII,

R cgHq; RIICOCGHEJ;

S-pyrrolidyl-l3fl-n-propyl 17,8 benzoyloxy-A des A-gonadiene, VIIa, R=C3Hq; R =COC H 3-halo-13fi-n-propyl 17B benzoyloxy 4,5 seco A gonadiene-S-one, VIII, R=C H R =COC H and particularly 3-chloro-13B n propyl-l7B-benzoyloxy- 4,5-seco-A -gonadiene-5-one;

13,H-n-propyl-l7,8-benzoyloxy 4,5 seco gonane 3,5-

dione, X, R c H R =COC H The following examples given as purely indicative enable a better comprehension of the invention. It is to be understood that corresponding procedures known to those skilled in the art may be employed. The temperatures are indicated in degrees centigrade. The melting points are the instantaneous melting points determined on the Kofier block.

EXAMPLE I Preparation of 2-Cyano-2-n-Pr0pyl-6-Meth0xy- T etralone-I 1 gm. of 6-methoxy-3,4-dihydronaphthyl-(2,l)-isoxazole, melting at 60 C. obtained according to Banerjee et al., I. Am. Chem. Soc., 78, 3769 (1956), were introduced under an atmosphere of nitrogen into 1.5 cc. of methanol. 3 cc. of sodium methylate containing 77.5 mgm. of sodium per cc. were added very slowly. The temperature of the mixture rose and after several minutes a rose-colored precipitate was formed. The mixture was agitated at 2025 C. for ten minutes, then 2.1 cc. of n-propyl iodide were added very slowly. After four hours of agitation under an atmosphere of nitrogen at room temperature, the mixture was heated to reflux for thirty minutes, then cooled and poured into water. The aqueous mixture was extracted with methylene chloride. The extracts were combined and concentrated under vacuum. The concentrate was taken up in ether and extracted with N/S sodium hydroxide in order to eliminate the 2-cyano-6-methoxy-tetralone-1. The ethereal solution was washed with water and dried. After evaporation of ether, the residue was crystallized from petroleum ether and 2-cyano-2-n-propyl-6-methoxy-tetralone-l, melting at 97", was recovered.

Ultraviolet spectra (in ethanol): e=l1,300; A 287 III/1., e:17,100.

The product, which was present in the form of white max.

needles, was .very soluble in alcohol, acetone, benzene and chloroform, soluble in hot ether and insoluble in water and dilute aqueous acids and alkalies.

Analysis.C I-I O N; molecular weight:243 .3. Calculated: C, 74.04%; H, 7.04%; N, 5.76%. Found; C, 74.2%; H, 6.8%; N, 6.0%.

This product is not described in the literature.

EXAMPLE II Preparation of Z-Cyano-Z-Allyl-6-Meth0xy- T etralone-Z II 1 gm. of 6-methoxy-3,4-dihydronaphthyl-(2,1)-isox azole, melting at 60 C. obtained according to Banerjee et al., J. Am. Chem. Soc., 78, 3769 (1956), were introduced under an atmosphere of nitrogen into 1.5 cc. of methanoh 3 cc. of sodium methylate containing 77.5 rngm. of sodium per cc. were added very slowly. The temperature of the mixture rose and after several minutes a rose-colored precipitate was formed. The mixture was agitated at 2025 C. for ten minutes, then 1.6 cc. of allyl bromide were introduced very slowly. The rosecolored precipitate dissolved little by little and the reaction mixture became colorless. The mixture was agitated under an atmosphere of nitrogen at room temperature for four hours. 10 cc. of water were then added to the mixture. and the aqueous mixture was extracted with methylene chloride. The combined extracts supplied, on evaporation to dryness under vacuum, 1.110 gm. of raw 2-cyan0:2-allyl-6-methoxy-tetralone-1. This compound was purified by recrystallization from isopropyl ether and from methanol. Yield: 0.810 gm. (being 68%) of 2- cyano-2-allyl-6-rnethoxy-tetral0ne-1, melting at 88.

The product was in the form of needles and Was very solublelin chloroform, soluble in alcohol and ether, and insoluble in water and dilute aqueous acids and alkalies.

Analysis.-C H O N; molecular weight=241.28. Calculated: C, 74.66%; H, 6.26%; N, 5.80%. Found: C, 74.8%; H, 6.1%; N, 6.1%.

Ultraviolet spectra (in ethanol): k 228 III/1.,

e=10,700; Amax. 289 m e=17,300; A 244 III/L, e=1,090.

Infrared spectra: Bands at 1,642 cm.- 925 cm? and 990 CH1. 1.

This product is not described in the literature.

EXAMPLE III Preparation of 2-Cyan0-2-n-Propyl-6-Meth0xy-Tetralone-1 by Hydrogenation of 2Cyano-2-Allyl-6-Methoxy-Tetralone-l 15 cc. of ethanol and 0.190 gm. of palladized carbon black (containing 16% palladium) previously reduced by hydrogenation, were added to 0.300 gm. of 2-cyano- 2-allyl-6-methoxy-tetralone-1, obtained according to Example II. The mixture was subjected to hydrogenation for five minutes. The catalyst was removed by vacuum filtration, the ethanolic solution was concentrated under vacuum and 0.300 gm. of raw 2-cyano-2-n-propyl-6- methoxy-tetralone-l were obtained. The raw compound was recrystallized from petroleum ether and methanol. Yield: 0.260 gm. of product melting at 97, identical to the compound prepared in Example I.

EXAMPLE IV By; condensing, according to the method of operation described in Example I, 6-methoxy-3,4-dihydronaphthyl- (2,1)-isoxazole .With l-bromo-l-benzyloxy-methane there was obtained 2-cyano-2-benzyloxymethyl-6-methoxytetralone-l.

EXAMPLE V Condensation of Z-Cyano-Z-n-Propyl-6-ZVIet/zoxy-Tetrczlone-1, II, With Dimethyl Succinate 5.9 gm. of potassium were dissolved in 200 cc. of

anhydrous t-butanol at reflux, the solution was concentrated to half the volume byndistillation under Vacuum. The temperature Was then adjusted to 20 C. and a solution of 9 gm. of Z-cyano-2-n-propyl-6-methoxytetralone-l (11), prepared according to Examples I or III, in 36 cc. of dimethyl succinate and 18 cc. of anhydrous t-butanol were introduced in the space of 3 hours.

The reaction mixture was agitated 17 to 18 hours at room temperature under an atmosphere of nitrogen. Concentrated hydrochloric acid was next added with cooling until the pH reached 1. The mixture was agitated for one hour until carbon dioxide ceased to evolve. Thereafter, the mixture was alkalized by addition to a potassium hydroxide solution. The mixture was then poured into a mixture of Water, ice and ether and extracted with ether. The ethereal extracts were washed with a sodium hydroxide solution, with water, dried and evaporated to dryness. The residue was crystallized from ether to give crystals of S-methoxy-lSfi-n-propyl-lS-methoxyearbonyl- E -des A-gonatetraene-U-one, III, R=C H melting at 96-97" C. These crystals occurred in the form of white crystals soluble in warm ether, ace-tone, benzene, chloroform, slightly soluble in alcohol and insoluble in water and dilute aqueous acids and alkalis.

Ultraviolet spectra: li at 308 mu, e=12,800; Amax, at 203 Ina, 10,200.

This compound is not described in the literature.

EXAMPLE VI Reduction With Saponification of 5-Methoxy-13fi-n- Propyl-15-Meth0xycarb0nyl-A -Des A-Gonatetraene-17-0ne, III, R=C H 2.5 gm. of Compound III, obtained according to the preceding example, Were dissolved in 35 cc. of tetrahydrofuran. 25 cc. of distilled water and 0.25 cc. of a normal sodium hydroxide solution were added, then 0.13 gm. of

sodium borohydride, were introduced. The reaction mixture was heated to 45 for four hours. 2.8 gm. of potassiurn hydroxide were then added and the mixture was heated for one hour at 60 C. Thereafter, the tetrahydrofuran was distilled for a period of about one hour in order to attain C. The heating was continued for one hour at this temperature. The orange solution thus obtained was acidified after cooling to a pH of 5 by addition of acetic acid and S-methoxy-13p-n-propyl-15-carboxy-A des A-gonatetraene-Ufl-ol, IV, 'RZC3H7, precipitated. This product was vacuum filtered, recrystallized from methylethylketone and a white product was obtained which melted at 181, then 195l96. It was very soluble in alcohol, soluble in dilute aqueous alkalis, in methylethylketone and in warm acetone, insoluble in Water, benzene, chloroform and dilute aqueous acids.

Analysis.-C H O molecular wei-ght:302.36. Ca1- culated: C, 71,49%; H, 7.33%. Found: C, 71.4%; H,

Ultraviolet spectra (in ethanol) 2. A 223 m e=l1,400; A 251 III/1., e=4,600;" A 298- m e=11,700.

This product is not described in the literature.

EXAMPLE VII Resolution of 5 Methoxy 13,8-11 Propyl 15 Carboxy- A -Des A-G0natetraene-17fi-Ol, IV, R=C H 8.2 gm. of S-methoxy-13/3-n-propy1-15-carooxy-A des A-gonatetraene-17B-ol, IV, R=C H prepared according to the preceding example, and 6.1 gm..of the dextrorotatory base of chloramphenicol were dissolved in 123 cc. of methanol. 165 cc. of isopropyl ether were added and the mixture agitated for ten minutes. 82 co. more of isopropyl other were added and the agitation was continued with cooling for oneahalf hour. Hie precipitated salt was next vacuum filtered to obtain 6.8 gm. (being yield) and it was recrystallized from water. The salt had a melting point of -135 C., and a specific rotation [oc] =-50 (c.=1% in methanol).

The salt obtained was dissolved in 40 volumes of water, acidified to a pH of 4.8 by addition of acetic acid and agitated for one hour while cooling to C. to C. The levorotatory enantiomorp-h of 5-methoxy-l3fi-npropyl-15-canboxy-A -des A-gonatetraene-lm-ol, IV, R=C H precipitated. It was vacuum filtered and washed with water in order to recover the desired product in purified form having a melting point of 213-214" C. and a specific rotation [a] =153154 (c.=l% in methanol).

The product was present in the form of white prisms, very soluble in alcohol, soluble in dilute alkalis and in warm acetone, very slightly soluble in ethyl acetate, insoluble in benzene, chloroform, ether, water and dilute aqueous acids.

Ultraviolet spectra: Identical with the racernic compound.

this compound is not described in the literature.

EXAMPLE VIII 3.5 gm. of levorotatory acid-alcohol IV were dissolved in 35 cc. of ethanol. The solution was heated to refiux under an atmosphere of nitrogen and a colorless limpi-d solution was obtained. 3.5 cc. of 22 B. hydrochloric acid were added and the heating at reflux was continued runder agitation for an hour. After cooling, the solution was poured on to a mixture of water and ice containing 4 cc, of sodium hydroxide solution, then the precipitated product, S-methoxy-l3,8-n-propyl-A des A-gonatetraene-l7/3-ol, V, R CfrL, was vacuum filtered. The product was recrystallized from alcohol. Compound V was obtained, having a melting point of l67l67.5 C. and a specific rotation [u] =-11l (c.:1% in methanol). The product was present in the form of colorless needles, very soluble in acetone, benzene, chloroform, soluble in alcohol, isopropyl ether and ethyl ether, and insoluble in water or dilute aqueous acids and alkalis.

Ultraviolet spectra (in ethanol): A 265 mu, e=18,500; A 298 m e:3,l20; A 307 mu, =2,400.

This compound is not described in the literature.

EXAMPLE 1X Reduction of the A1465) Double Bond of5-Methoxy-13fln Propyl M Des A-Gonatetraene-J 7 8-01, V, R=C3H7 The catalyst was previously prepared in the following manner:

A mixture containing 1 gm. of activated carbon, 1 cc. of a solution containing 20% palladium chloride and 50 cc. of water were agitated under hydrogen. The agitation was continued for one hour. The mixture was then alkalinized to a pH of 9 by additon of normal sodium hydroxide solution, then agitated again for a period of an hour under hydrogen. The product was vacuum filtered and washed with water and dried under vacuum.

2.3 gm. of 5 methoxy l3fi-n-propyl-N -des A- gonatetraene-Ufi-ol, prepared according to the preceding example, were dissolved in 50* volumes of ethanol, then 0.57 gm. of pmladized carbon black prepared as above in 5 volumes of ethanol were added and the mixture was agitated under hydrogen for a period of thirty minutes. The catalyst was then vacuum filtered from the mixture. The filtrate was evaporated under vacuum to dryness and an oil residue was obtained which consisted of raw 5 methoxy-l3fi-n-propyl-A -des A-gonatriene'l7 6-ol, VI, R=C H i This product VI could be purified by formation of its formiate. This process was as follows:

Compound VI, obtained starting from 2.3 gm. of Compound V, was dissolved in 9.2 cc. of formic acid. It was heated to 85 under an atmosphere of nitrogen under agitation and the heating was maintained for a period of twenty minutes. After cooling, it was poured on a mixture of water and ice, agitated for a period or" one hour. Then the formiate of Compound VI was vacuum filtered. 5 methoxy 13/3 n-propyl-17t3formyloxy-A -des A- gonatriene was recrystallized from isopropyl ether and had a melting point of 77 C. and a specific rotation [a] =57.5 (c.=1% in chloroform). The product was present in the form of White prismatic needles, very soluble in acetone, benzene and chloroform soluble in alcohol, isopropyl and ethyl ethers and insoluble in water and dilute aqueous acids.

Ultraviolet spectra (in ethanol): 6:2,120, t 289 m 5:2,000.

This compound is not described in the literature.

The forrniate of Compound VI was placed in suspension in 10 volumes of methanol, then drop by drop there was introduced one volume of a solution containing 700 g./l. of potassium hydroxide. The reaction mixture was agitated for a period of one hour in an atmosphere of nitrogen at room temperature. The mixture was next poured on water and extracted with ether. The ethereal extracts were washed with water, the ether removed under vacuum and several entrainments with methylene chloride were made in order to dry the compound.

A practically theoretical yield of S-methoxy-BB-npropyl-A -des A-gonatriene-lZB-ol, VI, RZC3H7, was obtained.

max.

EXAMPLE X 0.78 gm. of sodium were introduced into 60 cc. of liquid ammonia at 75 C. The mixture was agitated for one hour at 75 then by small fractions in the space of three hours 1.52 gm. of S-methoxy-l3B-n-prop'yl-A des A-gonatriene-l7fi-ol, prepared according to the preceding example, dissolved in 30 cc. of other, were added. The mixture was energetically agitated at 75 for a period of one hour, then cc. of ethanol were added. The external cooling was stopped and the mixture was allowed to warm progressively to room temperature with elimination of ammonia. 100 cc. of methylene chloride were added to the mixture under nitrogen, then cc. of distilled water were added. The mixture was agitated, allowed to decant and the aqueous phase drawn oil. The operation was repeated several times. 75 cc. of 22 B. hydrochloric acid in 150 cc. of methanol were next introduced into the organic phase, always under nitrogen. The methylene chloride and other were removed by vacuum distillation, then the temperature of the mixture was raised to 70 C. under agitation for a period of ten minutes. The mixture was next poured into a solution of sodium bicarbonate and extracted with methylene chloride. The organic extracts, after washing with water and drying, were concentrated to dryness and a residue was obtained which consisted of raw 13,8-n-propyl-A -des A- gonene-l7fi-ol-5-one, VII, R= C H R =H. This product was suspended in petroleum ether, heated to reflux, iced, and the precipitate was vacuum filtered and recrystallized from isopropyl ether. The purified product VII had a melting point of l40.5142 C. and specific rotation [a] :-4O (c.=l% in methanol).

The product was present in the form of colorless needles, very soluble in acetone and chloroform, soluble in alcohol, benzene and ethyl acetate, slightly soluble in ether and insoluble in water and dilute aqueous acids and alkalis.

Analysis.-C H O molecular weight=2 48.34. Calculated: C, 77.38%; H, 9.74%. Found: C, 77.4%; H, 9.7%.

Ultraviolet spectra (in ethanol): i 240 mu, 216,200.

This product is not described in the literature.

ll EXAMPLE xr Esterification of 13,8 n-Prpyl-A -Des A-Gonene-IZB-Ol- S-One, VII, R=C3H7, R =H 1 gm. of raw 13/3-n-propyl-A -des A-gonene-17B-ol-5- one, VII, RIC3H7, R =l-I, melting at 138, prepared according to the preceding example, was dissolved in volumes of pyridine. The solution was cooled to C. and drop by drop under an atmosphere of nitrogen and under agitation, 1.5 cc. of benzoyl chloride were introduced. The mixture was agitated for a period of fifteen minutes, then allowed to remain for a period of ten hours at [5 under an atmosphere of nitrogen. 1.25 cc. of formic acid were next added with cooling. The mixture was agitated, then poured into a solution of sodium bicarbonate. After an hour of agitation, the 13B-n-propyl-l7fl-benzoyloxy-A -des A-gonene-S-one, VII, R=C3H7, R =C0C H was vacuum filtered. The compound was washed with water and dnied over phosphorus pentoxide. On recrystallization from ethanol, then from petroleum ether, the desired product in purified form was obtained having a melting point of 112.5 C. and a specific rotation [oz] =|26 (c.=1% in methanol).

The product was present in the form of colorless rhombohedral crystals, very soluble in acetone and chloroform, soluble in alcohol, isopropyl ether and ethyl ether and insoluble in water and dilute aqueous acids or alkalis.

Analysis.-C H O molecular weight=352.45. Calculated: C, 78.37%; H, 8.01%. Found: C, 78.3%; H, 7.9%.

Ultraviolet spectra (in ethanol): xmax, 235 my, e=30,000; A 281 my, 6:790; inflexion 273 III/L, E=1,080.

Infrared spectra (in CS conjugated ketone at 1676 CIILTI; conjugated ketone at '1615 CHLTI; CI-I:C at 887 cmf r This product is not described in the literature.

EXAMPLE XII Preparation of the Enamine of Z3fl-n-Propyl 17-Benzoyloxy A Des A-GoneneJ-One, VII, RIC3H7, R '=COC H 0.500 gm. of l3/8-n-propyl-17fl-benzoyloxy-A -des A- gonene-S-one, VII, R=C H R =COC H were introduced into 1 cc. of pyrrolidine and heated to 80-85" C. for a period of five minutes under an atmosphere of nitrogen. After cooling, 4 cc. of methanol were added. The pyrrolidyl-enamine, 5 pyrrolidyl-l3,8-n-propyl-17fl-benzoyloxy A des A gonadiene 5 one, VI-Ia, R:C H R =COC H started to crystallize. The mixture was agitated for a period of an hour under nitrogen, then several more cc. of methanol were added and the mixture so obtained was allowed to stand for a period of one-half hour at 0. The product was next vacuum filtered, washed with methanol and dried under vacuum. Compound VIIa, R=C H R =COC H was thus obtain having a melting point of 118-119" C. and a specific rotation [u] =+l38 (c.=1% in benzene). The product was present in the form of pale yellow needles, very soluble in benzene and chloroform, soluble in acetone, slightly soluble in ether. It was decomposed in Water and in dilute aqueous acids or alkalis.

Analysis.C H O N; molecular weight:405 .5 Cal culated: C, 79.96%; H, 8.70%; N, 3.45%. Found: C, 79.9%; H, 8.7%; N, 3.2%.

Ultraviolet spectra (in ether): A 229 m e:16,l00; A 281 m e=26,100.

This compound is not described in the literature.

EXAMPLE XIII Condensation of the Enamine, 5-PyrrolidyZ-HB-n-Propyl- Ups-Benzoyloxy A -Des A-Gonadiene, VIIa R:'C H R :COC H With Dichlorobutene 0.400 gm. of the enamine, S-pyrrolidyl-l3/3 11-propylu,iis,

17/3 benzoyloxy A des A-gonadiene, VIIa, R:C I-I R =COC H produced according to the preceding example, and 0.190gm5ofpotassium iodide were introduced into 3.2 cc. of 'dimethylformamide. 0.26 cc. of 1,3-di-chlorobutene-2 were added and the mixture formed was agitated for a period of two hours under an atmosphere of nitrogen at room temperature. About 1 cc. or" water was next added, the mixture allowed to stand ten hours at 0 'C., then poured into water and extracted with ether. The ethereal extracts, after washing with water, were evaporated to dryness under vacuum. The residue consists of the raw 3-chloro-13fi-n-propyl-17flbenzoyloxy-4,5-seco-A -gonadiene-5-one, VIII, R=C H R =COC H X=Cl, which was purified by chromatography through parts of silica gel. After withdrawing 3.5 to 4% of a first elution with methylene chloride containing 0.2% of acetone, the desired product was eluted with methylene chloride containing 0.4% of acetone. This product was utilized without other purification in the course of the synthesis.

The product, which was present in the form of a colorless oil, was soluble in alcohol, acetone, benzene and chloroform, slightly soluble in isopropyl or ethyl ether, and insoluble in water.

This compound is not described in the literature.

EXAMPLE XIV Hydrolysis of 3-Chloro-13fim-Propyl-17(3-Benzoyl0xy-4, 5 Seco A Gonadiene 5 One, VIII, R caHq, R =COC H X=Cl 0.380 gm. of 3-chloro-13fl-n-propyl-l7fi-benzoyloxy-4, 5-seco-A -gonadiene-5-one, VII, R=C H- R =COC H X=Cl, were dissolved in 0.4 cc. of anhydrous ether, cooled to +5 C., then 3.5 cc. or concentrated sulfuric acid were added. The resultant clear brown solution was poured into a mixture of cc. of a 10% aqueous solution of sodium bicarbonate and 70 cc. of methylene chloride. This mixture was agitated for several minutes, then extracted with methylene chloride. The extracts were washed with water, then dried and evaporated to dryness under vacuum. A gummy product was recovered which comprised 13;; n propyl-l7B-benzoyloxy-4,5-seco-A gonene-3,5-dione, IX, R cgH R =COC3H which was purified by chromatography through 80 pants of silica gel. After withdrawing 9.3% of the product as a first elution with methylene chloride containing 1% of acetone, 82.5% of 13fi-n-propyl-l7B-benzoyloxy-4,5-seco-A gonene-3,5-dione were eluted with methylene chloride containing 1.5% of acetone. The product was present in the form of a colorless oil, soluble in alcohol, acetone, benzene, chloroform, slightly soluble in isopropyl and ethyl ethers, insoluble in water. It was decomposed by dilute aqueous acids or alkalis.

Ultraviolet spectra (in ethanol):

h 238 my, Ei f =5ll A 250 m E}% =417 This compound is not described in the literature.

EXAMPLE XV 0.15 gm. of activated carbon, 6 cc. of water and 0.15 cc. of hydrochloric acid solution containing 20% of palladium chloride were mixed together. The mixture was aikalinized by addition of normal sodium hydroxide solution to give a pH of 9. The palladized carbon black was vacuum filtered, washed with water and dried under vacuum; then it was placed in suspension in 2 cc. of ethanol and agitated in the presence of hydrogen. To the suspension of catalyst, 0.244 gm. of l3fi-n-propyl-l7fibenzoyloxy-4,5seco-A -gonene-3,5-dione. in solution in 5 cc. of ethanol were added and the mixture was agitated 13 under hydrogen for a period often to fifteen minutes until the absorption of the theoretical quantity of hydrogen. The catalyst was next removed by vacuum filtering and the ethanol evaporated under vacuum. The residue was chromatographed through 80 parts of silica gel and eluted with methylene chloride containing 1.5% of acetone. 13B-n-propyl-17,9-benzoyloxy 4,5 seco-gonane-3,5-dione, X, R=C I-I- R '=COC H was obtained. This compound was present in the form of a colorless oil, soluble in alcohol, ether, acetone, benzene, chloroform, and insoluble in water.

Ultraviolet spectra (in ethanol):

mnx. y; This compound is not described in the literature.

EXAMPLE XVI Preparation of the Benzoic Acid Ester f 18,19-Di-N0r- 13,8-n-Pr0pyl-Testosterone 0.100 gm. of 13/3-n-propyl-17e-benzoyloxy-4,5-secogonane-3,5-dione, prepared according to the preceding example, were dissolved in 2 cc. of acetic acid under an atmosphere of nitrogen, 0.15 cc. of 22 B. hydrochloric acid were added and the mixture was allowed to remain in a closed vessel in total darkness for a period of fourteen hours at room temperature. A clear, green, limpid solution was obtained to which a solution of sodium bicarbonate was added to raise the pH to 5. Thereafter, the solution was extracted with methylenetchloride. The extracts were washed with water, dried, then evaporated to dryness under vacuum. The residue was crystallized from isopropyl ether. It was recrystallized from ethyl acetate and the benzoic acid ester of 13,6-n-propyl- 18,19 di-nor-testosterone (Compound XI, R=C H R -=COC H was obtained, having a melting point of 148 C. and a specific rotation [a] =+99 (c.=1% in methanol).

The product was present in the form of colorless needles, soluble in acetone, alcohol, benzene, chloroform, slightly soluble in ether and ethyl acetate and insoluble in water and dilute aqueous acids and alkalis.

Analysis.--C I-I O molecular weight=406.5. Calculated: C, 79.77%; H, 8.43%. Found: C, 79.8%; H, 8.4%.

Ultraviolet spectra (in ethanol): A 235 m 5: 27, 900; hmax' 280 III .t, 6:755.

The rotatory dispersion curve of the product is completely identical with that of the benzoic acid ester of 19-nor-testosterone.

The benzoic acid ester of 18,19-dinor-13B-n-propyltestosterone is not described in the literature.

By saponification, according to known procedures, of the benzoic acid ester of 18,19-dinor-13[3-n-propy1-testosterone, the free alcohol, 18,l9-di-nor-13B-n-propyl-testosterone, XI, R==C H R H, was obtained.

l8,19-di-nor-13fl'n-propyl-testosterone can be esterified by conventional means with esterifying derivatives of any of the acids above enumerated to obtain the ester of an organic carboxylic acid having from 1 to 18 carbon atoms. In addition, other Eli-substituted 18,19-di-nor-testosterones can be prepared by varying the alkylating agent, RX, as above described. It is also to be noted that 1,3- dihalo-butene-2 can be directly condensed with compounds of the Formula VII, that is to say, with a compound whose ketone in the 5-position has not previously been blocked in the form of an enamine, by operating in the presence of an alkaline condensation agent.

It is to be understood that the invention is not limited to the process of the examples given above and other expedients can be employed without departing from the spirit of the invention and the scope of the appended claims.

Id We claim: 1. A compound of the formula:

wherein R represents a radical selected from the group consisting of alkyl having from 2 to 18 carbon atoms, alkenyl having from 2 to 6 carbon atoms and phenylalkoxyalkyl having from 8 to 18 carbon atoms, and R represents a member selected from the group consisting of hydrogen and the acyl radical of an organic carboxylic acid having from 1 to 18 carbon atoms selected from the group consisting of alkanoic, alkenoic, cycloalkylalkanoic, arylalkanoic, and 3,5-dinitrobenzoic acids.

2. 2-cyano-2-allyl-6-methoxy-tetralone-1.

3. 2-cyano-2-benzyloXymethyl-6-methoXy-tetralone-l.

4. A compound having the formula:

wherein R represents a radical selected from the group consisting of alkyl having from 2 to 18 carbon atoms, alkenyl having from 2 to 6 carbon atoms and phenylalkoxyalkyl having from 8 to 18 carbon atoms, and R represents a member selected from the group consisting of hydrogen and the acyl radical of an organic carboxylic acid having from 1 to 18 carbon atoms selected from the group consisting of alkanoic, alkenoic, cycloalkylalkanoic, arylalkanoic, and 3,5-dinitrobenzoic acids.

5. The compound of claim 4 wherein R is the n-propyl radical and R is hydrogen.

6. The compound of claim 4 wherein R is the n-propyl radical and R1 is COCgHs.

7. A compound having the formula:

wherein R represents a radical selected from the group consisting of alkyl having from 2 to 18 carbon atoms, alkenyl having from 2 to 6 carbon atoms and phenylalkoxyalkyl having from 8 to 18 carbon atoms, and R represents a member selected from the group consisting of hydrogen and the acyl radical of an organic carboxylic acid having from 1 to 18 carbon atoms selected from the group consisting of alkanoic, alkenoic, cycloalkylalkanoic, arylalkanoic, and 3,5-dinitrobenzoic acids.

8. The compound of claim 7 wherein R is the n-propyl radical and R is COC H 9. The process of preparing a derivative of testosterone of the formula:

wherein -R represents a radical selected from the group consisting of alkyl having from 2 to 18 carbon atoms, alkenyl having from 2 to 6 carbon atoms and phenylalkoxyalkyl having from 8 to 18 carbon atoms, and R wherein R has the above assigned meaning with dimethyl succinate in the presence of an alkaline condensation agent;

(c) reacting the compound having the formula:

CH O

wherein R has the above assigned meaning with an alkali metal borohydride in an inert organic solvent at reflux temperatures;

(d) resolving the compound having the formula:

R on 6K7 coon ch 0 wherein R has the above assigned meansing by formation of an insoluble salt between a dextrorotatory base and the levorotatory enantiomorph, separating the insoluble salt and hydrolyzing the insoluble salt with an acid;

(e) heating the levorotatory enantiomorph to reflux in an inert solvent with hydrochloric acid;

(f) reducing the compound having the formula:

1 o CH wherein R has the above assigned meaning by cata lytic hydrogenation; (g) reacting the compound having the formula:

wherein R has the above assigned meaning with sodiurn in liquid ammonia; (h) esterifying the compound having the formula:

1% wherein R has the above assigned meaning and R represents hydrogen by reaction with an esterifying derivative of an organic earboicylic acid having from 1 to 13 carbon atoms selected from the group consisting of alkanoic, alkenoic; cycloalkyl-alkanoic, arylalkanoic, and 3,5-dinitrobenzoic acids; (1') reacting the compound having the formula:

wherein R has the above assigned meaning and R represents the acyl radical of an organic carboxylic acid having from 1 to 18 carbon atoms selected from the group consisting of alkanoic, alkenoic, cycloalkylalkanoic, arylaik-anoic, and 3,5-dinitrooenzoic acids, with pyrrolidine; v

(j) reacting the compound having the formula:

wherein R and R have the above assigned meanings with a 1,3-dihalo-2-butene; I (k) hydrolyzing the compound having the formula:

wherein R and R have the above assigned meanings and represents a halide with a strong acid;

(I) reducing the double bond in the compound having the formula:

wherein R and R have the above assigned meanings by catalytic hydrogenation; v (m) reacting the compound having the formula:

Ono

wherein R and R have the above assigned meanings With a strong acid, and (n) recovering said derivative of testosterone.

10. The process of claim 9 (a) wherein said alkali metal lower alkanolate is sodium methylate and said halide is allyl halide.

11. The process of claim 9 ((2) wherein said alkali metal lower alkanolate is sodium methylate and said halide is n-propyl halide.

12. The process of claim 9 (a) wherein said alkali metal lower alkanolate is sodium methylate and said halide is 1-bromo-l-benzyloxy-rnethane.

13. The process of claim 9 (d) wherein said dextrorotatory base is dextrorotatory chloramphenicol.

14. The process of claim 9 (1) wherein said catalytic hydrogenation occurs in the presence of palladized carbon black.

15. The process of claim 9 (j) wherein said 1,3-dihalo- Z-butene is l,3-dichloro-2-butene.

16. The process of claim 9 (I) wherein said catalytic hydrogenation occurs in the presence of palladized carbon black.

17. The process of preparing 2-n-propyl-2-cyano-6- methoXy-tetralone-l which comprises dissolving 6-methoXy-3,4-dihydronaphthyl (2,1) isoxazole in methanol, reacting said solution with sodium methylate in methanol in an inert atmosphere and thereafter With allyl bromide, subjecting the 2-allyl-2-cyano-6-methoxytetralone-1 to the action of hydrogen in the presence of an hydrogenation catalyst and recovering 2-n-propyl-2-cyano-6-methoXy-tetralone- 1.

18. The process of preparing 2-n-propyl-2-cyano-6- methoxy-tetralone-l Which comprises subjecting 2-ally1-2- cyano-6-methoXy-tetralone-1 to the action of hydrogen in the presence of a reduced palladium catalyst and recovering said 2-n-propyl-2-cyano-6-methoXy-tetralone-1.

19. A compound of the formula References Cited in the file of this patent Banerjee et al.: J. Am. Chem. Soc., vol 78, pages 3769-3775 (1956).

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 5, 115 ,507 December 24, 1963 Gerard Nomin et a1.

It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 5, line 27, for "his" read This column 6, line 17, for "II" read III column 8, line 12, for "to" read of line 45, for "A -des" read A -des column 11, lines 40 and 41,: for "17- Benz'oyloxy", in italics, read l7B-Benzoyloxy in italics; column 12, line 32, for "VII" read VIII column 14, lines 4 to 9, the formula should appear as shown below instead of as in the patent:

column 15, line 41, for "meansing" read meaning Signed and sealed this 13th day of October 1964.

(SEAL) Attest:

ERNEST W. SWIDER EDWARD J. BRENNER At'testing Officer Commissioner of Patents Notice of Adverse Decision in Interference In Interference No. 94,918 involving Patent No. 3,115,507, G. Nomine, R. Bucourt and A. Pierdet, NEW ANALOGS OF IQ-NOR-TESTOSTER- ONE, THEIR ESTERS AND PROCESS OF PREPARATION, final judg' ment adverse to the patentees Was rendered July 30, 1969, as to claim 1..

[Official Gazette March 1'7, 1.970.] 

1. A COMPOUND OF THE FORMULA: 